The subject of the present invention relates to the development of a multiparticulate form of the controlled-release minigranule type for the oral route, allowing the administration, in a single daily dose, of a particular antidepressant, namely: Milnacipran.
The novelty of this invention rests on the design of this minigranule or minisphere form which, by a combination:
of the Milnacipran concentration per minigranule,
of the physicochemical characteristics of the coating film,
and of the thickness of this film,
makes it possible to control, surprisingly, the in-vitro release over several hours of a molecule whose aqueous solubility is close to 800 g/l, thereby making the single-dose administration of this entity possible.
Milnacipran and its Cis enantiomers exist in the form of hydrochlorides, whose aqueous solubilities are close to 800 g/l. Currently, these extremely soluble molecules, formulated with dicalcium phosphate, calcium carboxymethylcellulose and polyvinylpyrrolidone, packaged in gelatin capsules, do not allow this objective to be achieved since the in-vitro release from this 50 mg Milnacipran form is complete in thirty minutes thereby requiring the administration of a gelatin capsule in the morning and a gelatin capsule in the evening.
By contrast and surprisingly, the present invention relates to a prolonged-release galenic form, intended for oral administration in a single daily dose of 50 to 240 mg of Milnacipran, provided in a multiparticulate form combining a plurality of minigranules each containing an active minisphere comprising a sucrose and/or starch core having a particle size of between 200 and 2000 xcexcm and containing 150 to 1000 xcexcg of Milnacipran as well as a binding agent, each minigranule being coated with a film, based on at least one polymer insoluble in water but permeable to physiological fluids, having a thickness of between 20 and 100 xcexcm, said galenic form allowing an in-vitro release corresponding to the following pattern:
between 10 and 55% of the dose released in 2 hours,
between 40 and 75% of the dose released in 4 hours,
between 70 and 90% of the dose released in 8 hours,
between 80 and 100% of the dose released in 12 hours.
This minigranule form containing a dose of 60 mg to 240 mg, more precisely 120 mg of Milnacipran in racemic form, or a therapeutically equivalent dose of Dextrorotatory Cis derivative, allows the therapeutic activity to be maintained over the nychthemeron while leveling the values of the plasma concentrations.
It will be recalled first of all that Milnacipran, a new antidepressant (patents Nos. FR 2,508,035-EP 200,638 and FR 2,640,972), exhibits a novel pharmacological activity since it allows a mixed inhibition of the capture of noradrenaline and serotonin, with no effect on dopamine.
Its chemical structure reveals two asymmetric carbons which confer on the molecule a Cis and Trans type isomerism, for which it has been demonstrated that the two Cis enantiomers are the active forms, preferably obtained by synthesis.
It has also been demonstrated that for these Cis derivatives the dextrorotatory form is more active than the levorotatory form.
Accordingly, the subject of the present invention applies both to the racemic molecule Milnacipran, but also to the two Cis enantiomers, since the physicochemical properties involved in the diffusional processes from the form remain identical.
Milnacipran and its Cis enantiomeric forms exhibit an absolute bioavailability greater than 85% and a biological half-life of between 7 and 9 hours, these properties being entirely compatible, from the pharmacokinetic point of view, with the design of a one-dose-per-day prolonged-release form.
In general, two distinct steps should be considered in the technical production of the prolonged-release minigranules, namely:
the active minisphere production phase,
the active minisphere film-coating phase.
Several technologies can be used for the production of the active minispheres:
mounting in a pan which consists of sprinkling the active ingredient with the aid of a binder on the sucrose or sucrose and starch cores also called nonpareils;
mounting in a fluidized air bed which consists in spraying a solution or a dispersion of active ingredient with the aid of a binder on the bed of nonpareils. This spraying may be performed from the top toward the bottom, from the bottom toward the top (Wxc3xcrster method) or tangentially (rotor method). In the latter case, the active ingredient may be sprayed in solid form concomitantly with the wetting liquid, with the aid of a feed hopper;
rotogranulation which makes it possible to obtain spherical grains from a suitable active agent-excipient mixture over which a binding solution is sprayed. This technology can be performed using rotogranulators combined or otherwise with a fluidized air bed;
extrusion-spheronization which allows the production of spherical grains. It involves obtaining, starting with a suitable active agent-excipient mixture, a plastic mass after mixing with a binding solution.
The plastic mass is then extruded using various systems which make it possible to convey and/or extrude this mass (barrel extruder, gear, piston, single- or twin-screw extruder, with axial or radial extrusion).
The extrudates obtained are then spheronized in a suitable spheronizer.
Conventionally, two techniques are used for the production of coated minigranules:
pan: the uncoated active minispheres are introduced into a perforated or nonperforated pan. A solution or dispersion of coating is then sprayed over the bed of minispheres with the aid of a gun or nozzle and any other suitable system allowing the production of a continuous, uniform and reproducible film;
fluidized air bed: depending on the spraying mode chosen, the film-coating of the active minispheres may be carried out by xe2x80x9ctop-sprayxe2x80x9d, by xe2x80x9cbottom-sprayxe2x80x9d or by xe2x80x9ctangential-sprayxe2x80x9d. The latter two techniques give a more uniform, more continuous and more reproducible coating than the first technique.
The major problem with which persons skilled in the art are confronted for the development of a prolonged-release form in general and of the minigranule type in particular, is the aqueous a solucility of the molecule.
In the present case, Milnacipran as well as its active enantiomers are very easily soluble in water (solubility=800 g/l). It should be recalled that it is impossible to use the base forms for reasons of stability.
Indeed, it is known to persons skilled in the art that with such molecules, the formulator who has to develop a prolonged-release form is confronted with the following antinomic problem:
avoiding the phenomenon of sudden discharge which is very frequent with this type of molecule and which, in some cases, is synonymous with side effects,
and ensuring a perfect control of the release of the entire administered dose so as to avoid any loss of product.
Some formulators have solved this problem:
by combining within the same formulation several minigranule fractions (DE-3,941,703), an uncoated fraction providing the release during the first few minutes, and a fraction coated with a large amount of polymer controlling the diffusion during the subsequent hours,
or by combining within the same formulation minigranules with multilayer film-coatings (U.S. Pat. No. 4,894,240-WO-9 3097 67) or chemical compositions of coating polymers of a heterogeneous nature (EP-508 653-EP-0 322 277).
The present invention provides, through the design of this minigranule form for prolonged release of Milnacipran, having an aqueous solubility equal to 800 g/l, a solution which is less constraining for the developer.
Indeed, the formulas which are the subject of the present invention make it possible, through their design (content of active ingredient per minigranule, thickness of the film and composition of the film), to achieve an in-vitro release which is compatible with the therapeutic objective while using only one type of minigranules per formula.
It is very difficult, because of the absence of references, to describe, for a molecule with a solubility greater than 500 g/l, what would be the design for a minigranule form manufactured by the fluidized air and/or pan technology.
By way of comparison, reference may be made to the publication xe2x80x9cChlorpheniramine maleate controlled release spheres, Ixe2x80x94Effect of ethyl cellulose and dibutyl sebacate levelsxe2x80x9d, A. R. Oritz LABRADOR, E. S. CHALY (#1146), Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 20, 1993 where the authors apply up to 30% Ethyl cellulose combined with Dibutyl sebacate in order to obtain a delayed release profile.
In patent EP-350 246, an organic base is used as release modulating agent.
In patent WO-953 491, inorganic bases are used as supports controlling the release.
In the document WO-9 201 446, hydrophobic substances (paraffin, waxes, stearyl alcohol) combined with a film of an acrylic nature are used to control the release of soluble active agents such as salbutamol, chlorpheniramine maleate.
It is obvious for persons skilled in the art that this type of formulation is very difficult to produce in and to transpose to a fluidized air bed.
In patent EP-249 949, the formulator produces a premix of soluble molecule with a nonionic polymer and an inorganic filler, before spraying them on the nonpareil, on which they then apply the insoluble film. In this example, there is in fact an intermediate layer limiting the diffusion of the active ingredient toward the coating film.
The solution proposed in the context of the present invention is much simpler and more easily industrializable, as shown more particularly in Examples Nos. 13, 14 and 15 below, because it provides a minigranule form composed of a single type of spheroids:
whose non-film-coated core has a size advantageously between 710 and 850 xcexcm,
whose active ingredient content per minigranule is preferably close to 510 xcexcg,
and whose film-coating based on ethyl cellulose in ethanolic solution is advantageously between 4% and 12.5%, that is to say a low thickness of 20 xcexcm to 80 xcexcm per minigranule.
Other characteristics and advantages of the present invention will be even understood on reading the detailed description given below, especially with regard to a number of specific exemplary embodiments.
The components which can be used for mounting Milnacipran in a pan are:
minispheres composed of sucrose and/or starch, also called nonpareils. These nonpareils were obtained by successive depositions of sucrose and/or starch on a sucrose crystal. The nonpareils used are preferably composed of 75% sucrose and 25% starch.
The nonpareils have various sizes ranging from 200 microns to 2 mm.
The nonpareils used preferably have a size of between 500 and 1000 microns and more particularly between 710 and 850 microns.
a binding agent sprayed in solution on a bed of minispheres. This binding agent may be a cellulose derivative such as hydroxypropylmethylcellulose, methyl cellulose, hydroxypropylcellulose, carboxymethylcellulose, may be gelatin, may be a solution of sucrose, may be a gum such as gum arabic, gum tragacanth, guar gum, pectins and alginates. It may be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights.
The amount of these binders in the wetting solution may be up to 3 to 50%, and in the finished product from 0.5 to 30%.
The binder used is preferably polyvinylpyrrolidone having a molecular weight of close to 50,000 Da (type K30) in an amount of 20% in the wetting solution and in an amount of 2 to 4% in the active minispheres.
the solvent used to carry the binder may be an organic solvent of the type including methylene chloride, acetone, an alcohol such as isopropanol or ethanol, purified water or miscible combinations of these different solvent. The solvent used is preferably ethanol.
an agent intended to avoid the agglomeration of the minigranules to each other is advantageously used by sprinkling on the bed of cores.
Silica derivatives, metal oxides such as titanium oxide, silicates such as talc may be used in amounts of between 0.5 and 20% of the weight of the active minispheres. The talc is preferably used in an amount of between 3 and 4%.
Milnacipran is sprinkled on the bed of cores and its amount may be between 5 and 90% in the minispheres. This amount is preferably between 45 and 55% and is preferably 51%. That is to say a Milnacipran concentration per minigranule of between 450 xcexcg and 550 xcexcg and preferably of close to 510 xcexcg since the active minisphere preferably weighs 1 mg.
The components used during the mounting of Milnacipran in a fluidized air bed are:
minispheres composed of sucrose and/or starch, also called nonpareils. These nonpareils were obtained by successive depositions of sucrose and/or starch on a sucrose crystal. The nonpareils used are preferably composed of 75% sucrose and 25% starch.
The nonpareils have various sizes ranging from 200 xcexcm to 2 mm.
The nonpareils used preferably have a size of between 500 and 1000 xcexcm and more particularly between 710 and 850 xcexcm.
a binding agent sprayed in solution on the bed of minispheres. This binding agent may be a cellulose derivative such as hydroxypropylmethylcellulose, methyl cellulose, hydroxypropylcellulose, carboxy-methylcellulose, may be gelatin, may be a solution of sucrose, may be a gum such as gum arabic, gum tragacanth, guar gum, pectins and alginates. It may be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights.
The amount of these binders in the wetting solution may be up to 3 to 50%, and in the finished product from 0.5 to 30%.
The binder used is preferably polyvinylpyrrolidone having a molecular weight of close to 50,000 Da (type K30) in an amount of 0 to 20% and more precisely 6.7% in the wetting solution and from 5 to 25%, more precisely 15.4%, in the active minispheres.
The solvent used to carry the binder may be isopropanol and/or acetone, ethanol and/or acetone and is preferably isopropanol.
The Milnacipran is sprayed in the form of a dispersion in an amount of 10 to 40% in the solvent. Its preferred amount is 20% in the solvent.
The Milnacipran may represent 5 to 90% of the active minisphere. It is preferably between 40 and 50% and is preferably 46%.
That is to say a Milnacipran concentration per minigranule of between 150 and 185 xcexcg and preferably of close to 170 xcexcg when the nonpareils have a size of between 500 and 600 xcexcm.
That is to say a Milnacipran concentration per minigranule of between 440 and 555 xcexcg and preferably of close to 510 pig when the nonpareils have a size of between 710 and 850 xcexcm.
That is to say a Milnacipran concentration per minigranule of between 680 and 850 xcexcg and preferably of close to 780 xcexcg when the nonpareils have a size of between 850 to 1000 xcexcm.
The components used during the production of active minispheres during extrusion-spheronization are:
A diluent which may be of a hydrophilic or hydrophobic nature.
The component hydrophilic diluent may be of a cellulosic nature, such as microcrystalline cellulose, sodium cellulose or even hydroxypropylmethylcellulose. Lactose and starch may also be used.
The lipophilic diluent may be a monoglyceride, a diglyceride or a triglyceride.
These diluents represent 5 to 90% of the active minisphere. The diluent preferably used is microcrystalline cellulose in an amount of between 25 and 75% and preferably in an amount of 50%.
A binding agent. This binding agent may be a cellulose derivative such as hydroxypropylmethylcellulose, methyl cellulose, hydroxypropylcellulose, carboxymethylcellulose, may be gelatin, may be a, solution of sucrose, may be a gum such as gum arabic, gum tragacanth, guar gum, may be pectins or alginates. It may be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights.
The amount of these binders in the wetting solution may be up to 0 to 50%.
This binding agent may vary from 0 to 20% in the active minispheres.
When the diluent is microcrystalline cellulose, it is not necessary to use a binding agent.
A solvent is used to wet the mixture of the different components and to make it an extrudable mass.
Alcohols such as ethanol or isopropanol may be used in combination or otherwise with purified water. Purified water is preferably used to wet the articles.
The active ingredient, during this operation, is introduced in an amount of between 5 and 90% of the weight of the active minispheres, preferably in an amount of between 25 and 75% of the weight of the active minispheres and more particularly of close to 50%. That is to say a Milnacipran concentration per minigranule preferably of between 250 and 750 xcexcm and more particularly 500 xcexcg.
The components used during the production of active minispheres during rotogranulation are:
A diluent which may be of a hydrophilic or hydrophobic nature.
The component hydrophilic diluent may be of a cellulosic nature, such as microcrystalline cellulose, sodium cellulose or even hydroxypropylmethylcellulose. Lactose and starch may also be used.
The lipophilic diluent may be a monoglyceride, a diglyceride or a triglyceride.
These diluents represent 5 to 90% of the active minisphere. The diluent preferably used is microcrystalline cellulose in an amount of between 40 and 60% and preferably in an amount of 50%.
A binding agent. This binding agent may be a cellulose derivative such as hydroxypropylmethylcellulose, methyl cellulose, hydroxypropylcellulose, carboxymethylcellulose, may be gelatin, may be a solution of sucrose, may be a gum such as gum arabic, gum tragacanth, guar gum, may be pectins or alginates. It may be derived from polyvidone such as polyvinylpyrrolidone of different molecular weights.
The amount of these binders in the wetting solution may be up to 0 to 50%.
This binding agent may vary from 0 to 20% in the active minispheres.
When the diluent is microcrystalline cellulose, it is not necessary to use a binding agent.
A solvent is used to wet the mixture of the different components and to make it an extrudable mass.
Alcohols such as ethanol or isopropanol may be used in combination or otherwise with purified water. Purified water is preferably used to wet the particles.
The active ingredient, during this operation, is introduced in an amount of between 5 and 90% of the weight of the active minispheres, preferably in an amount of between 40 and 60% of the weight of the active minispheres and more particularly of close to 50%. That is to say a Milnacipran concentration per minigranule preferably of between 500 and 750 xcexcm and more particularly 625 xcexcg.
The coating of the minispheres is composed of film-forming polymers insoluble in water but permeable to physiological fluids and which allow Milnacipran in solution to pass through by diffusion phenomena.
The coating agents traditionally used are derivatives of acrylic copolymers, alkyl celluloses, ethyl cellulose and lacquers of natural origin such as shellac gum.
Methacrylic copolymers of the poly(ethyl acrylate, methyl methacrylate) type in aqueous dispersion marketed under the name Eudragit NE30D, or of the poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride) type in organic solvents (RS100 or RL100) or in aqueous dispersion RS30D/RL30D whose permeability depends on the amount of ammonium groups (RI greater than RS) are used in the invention.
The polymers are used in amounts of between 5 and 50% by weight of dry polymer relative to the weight of the active minispheres.
The polymer which is commercially called Eudragit RL100 or RL30D is not used in these amounts but respectively in combination with the polymers commercially called Eudragit RS100 or RS30D in amounts which may range from 1 to 20% of the overall amount of coating polymers.
Other coating agents such as ethyl cellulose of different grades are used. In the invention, the ethyl cellulose may be used in solution in a solvent such as dichloromethane, ethyl acetate, methanol and ethanol or a mixture of these solvents. Ethanol is preferably used.
The amount of ethyl cellulose represents, by weight of dry polymer, 2.5 to 50% of the weight of the active minispheres and is preferably between 3 and 15% and more particularly between 4 and 12.5%.
The ethyl cellulose may also be in the form of a ready-for-use aqueous dispersion such as Aquacoat ECD30 or Surelease which differs, inter alia, from Aquacoat ECD30 by the fact that the plasticizer is integrated into the dispersion.
The aqueous dispersions of ethyl cellulose are used in amounts of solid substances representing from 5 to 30% of the weight of the active minispheres. The amounts used preferably represent 12.5 to 17.5% of these minispheres.
It is possible to combine with these dispersions low-molecular weight hydroxypropylmethylcelluloses which are soluble in water, polyvinylpyrrolidone, low-molecular weight polyethylene glycols or any other soluble substances capable of promoting the creation of pores in the membrane in amounts of between 1 and 20% of the coating film. In our case, no soluble polymer was integrated into the formula.
The coating polymers used in this study were combined with plasticizers intended to improve the formation and the quality of the film.
The plasticizers used may be: dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate, triacetin, polyethylene glycols propylene glycol, glycerols, glycerides such as acetylated monoglyceride, fractionated coconut oil and castor oil.
The plasticizers are used in amounts of between 0 and 50% of the weight of dry polymer.
They are preferably used in amounts of between 15 and 25% of the weight of dry polymer.
The plasticizer used is preferably triethyl citrate in an amount representing 20% of the weight of dry polymer.
Filling agents are used, such as metal oxides, silicas, silicates, in particular magnesium silicate, in amounts of between 10 and 100% of the weight of dry polymer.
The amounts used with the acrylic derivatives are preferably between 50 and 100% of talc whereas they are between 20 and 70% with ethyl cellulose in ethanolic solution and preferably equal to 50%.
Antifoaming agents, such as silicone derivatives, may be integrated into the various formulations in amounts of between 0 and 0.5% of the active minispheres.